The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on radiation inducible molecular targets that is, exploring the use of fractionated radiation to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy. In essence, radiation would set up the tumor for enhanced drug killing. This project has now demonstrated that different dose sizes of radiation (10 Gy x1, 2 Gy x5 and 1 Gy x10) produce different phenotypes. We have demonstrated that the cells post-radiation are more drug sensitive for at least 1 drug and much more work is in progress but we are now working on combinations of drugs. This work fits into molecular targeted cancer treatment using both the non-oncogene addiction targets and synthetic lethality We have made significant progress in studying the inducible mRNA, miRNA and proteins. We have expanded to add a p53 proficient cell line. Projects now in progress include studying metabolomic changes, in vivo SD and MF for PC3 cells, and exploring epigenetic changes. We are also identifying pathways to target and working on timing of radiation and drug(s). Indirectly related to this work are efforts being done in the Office of the Assistant Secretary for Preparedness and Response in Health and Human Services (HHS). I am heading a group developing civilian medical response planning for radiological and nuclear terrorism and other events. This involves planning, policy, and normal tissue injury-related science. Medical countermeasures are being developed through NIAID support in the Centers for Medical Countermeasures Against Radiation (CMCR). This overall program has major impact to U.S. preparedness and also has a spin-off for normal tissue injury from radiation and the potential for post-exposure mitigators and treatments. We are working with other agencies (NIAID and Dept of Defense) on the potential of bringing these mitigators into cancer care. The critical importance of the NCI- HHS linkage is bringing up-to-date scientficia thinking to medical countermeasure development and diagnosis